PDBsum entry 4djh

Hormone receptor/antagonist

PDB id

4djh

Contents

			Protein chain

					447 a.a.

			Ligands

					JDC ×2


					CIT


					OLC ×2


					PEG ×2

			Waters ×25

References listed in PDB file

Key reference

Title

Structure of the human κ-Opioid receptor in complex with jdtic.

Authors

H.Wu, D.Wacker, M.Mileni, V.Katritch, G.W.Han, E.Vardy, W.Liu, A.A.Thompson, X.P.Huang, F.I.Carroll, S.W.Mascarella, R.B.Westkaemper, P.D.Mosier, B.L.Roth, V.Cherezov, R.C.Stevens.

Ref.

Nature, 2012, 485, 327-332. [DOI no: 10.1038/nature10939]

PubMed id

22437504

Abstract

Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of κ-opioid receptor (κ-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR.



	Figure 3. Putative interaction modes of morphine-based high-affinity [kgr]-OR-selective antagonists nor-BNI and GNTI. a, b, Interaction modes of nor-BNI (a) and GNTI (b). Ligands are depicted as capped sticks with green carbons, and contact side chains of the receptor within 4 Å from the ligand are shown with grey carbons. Key hydrogen bonds and salt bridges are indicated with small cyan spheres and residues unique to the κ-OR are labelled in blue. Residue Asp 138^3.32, which also shows critical impact on GNTI and nor-BNI binding in mutagenesis studies, is highlighted in red. Ballesteros–Weinstein residue numbers are shown under the κ-OR residue numbers. The graphics were prepared using the ICM molecular modelling package (Molsoft LLC).		Figure 4. Model of covalently bound RB-64. a, b, Putative binding mode of the RB-64 +463 amu (a) and the RB-64 +431 amu (b) adduct. Residues within 4 Å of the ligand are shown. Ligand, capped sticks/cyan carbons; κ-OR side chains, capped sticks; hydrogen bonds, small green spheres; κ-OR-unique residues are labelled in blue. Ballesteros–Weinstein residue numbers are shown under the κ-OR residue numbers. The graphics were prepared using the ICM molecular modelling package (Molsoft LLC).

PROCHECK

	Headers